Nanomaterial technological development has been underway for decades. Only in the past decade has serious attention been paid to potential unwanted effects. Many nanomaterials do not readily dissolve or disintegrate in biological and environmental milieu. As a result, they persist for months to years where they are sequestered (in mammals, mostly in mononuclear phagocyte system organs such as the liver, spleen, and bone marrow), often associated with inflammatory/oxidative stress responses, including granuloma. These unwanted effects have been seen with nanoceria (nanoscale cerium dioxide). On the other hand, nanoceria has been shown to be an effective anti-inflammatory/antioxidant in numerous acellular, cell, and whole animal models of inflammation/oxidative stress. Nanoceria's pro- and antioxidant effects result from its auto-catalytic redox behavior (Ce(III) oxidation to Ce(IV); Ce(IV) reduction to Ce(III)). Specific aim 1 will determine if nanoceria can produce inflammatory/pro-oxidant effects in the absence of elevated inflammation/oxidative stress and anti-inflammatory/antioxidant effects when inflammation/oxidative stress is elevated, and determine the lowest observed adverse and lowest observed beneficial doses. Several nanoceria will be studied. Initially we will focus on the 5 and 30 nm ceria that we have extensively studied, to understand their behavior in the presence of elevated oxidative stress/inflammation. We will obtain from Sudipta Seal et al or prepare the ~ 8 nm ceria they are investigating and compare it to the 5 nm ceria for physicochemical similarities/differences, and determine its ability to produce the adverse effects we have seen with the 5 nm ceria. If the 5 and 8 nm ceria are not significantly different we will continue this project with the 5, but not 8, nm ceria. Due to the very low oral and pulmonary absorption of nanomaterials, nanoceria will be delivered intravenously to establish sufficient levels in multiple organs to study its biodistribution, persistence, biotransformation, and effects. Preliminary findings indicate that nanoceria undergoes some bioprocessing in mammals over months, to a more stable form. This appears to occur via dissolution and formation of very small nanoceria particles, which have a greater surface Ce(III) enrichment; therefore expected to have enhanced anti-inflammatory/antioxidant properties. This biotransformation suggests enhanced benefit over time associated with nanoceria's persistence and bioprocessing. Specific aim 2 will identify factors that contribute to nanoceria dissolution and precipitation and mediate its bioprocessing and precipitation in the liver. The proposed studies will test the hypothesis that the same nanoceria can both increase and decrease inflammation/oxidative stress depending on the initial level of stress, identify nanoceria doses that maximize its efficacy relative to its unwanted effects, and provide insight into its biotransformation that may enable safer by design nanoceria for use as a therapeutic agent with prolonged anti-inflammatory/antioxidant activity.